Dietary fiber and soy protein-based microbiome metabolites for IBD prevention

基于膳食纤维和大豆蛋白的微生物组代谢物用于预防 IBD

基本信息

批准号：
10607658
负责人：
GRACE Y. CHEN
金额：
$ 69万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607658
关键词：
Affect Amino Acids Animals Anti-Inflammatory Agents Bacteria Bacteroides Bacteroides thetaiotaomicron Butyrates Caseins Cells Chronic Disease Citrobacter rodentium Clinical Colitis Colon Colorectal Cancer Complex Complex Mixtures Consumption Data Defect Degradation Pathway Development Diet Diet and Nutrition Dietary Factors Dietary Fiber Digestion Disease Disease Progression Disease susceptibility Enteral Nutrition Environmental Risk Factor Epithelial Cells Epithelium Equilibrium Etiology Fermentation Fiber Foundations Genetic Genetic Polymorphism Genetic Predisposition to Disease Germ-Free Glycoproteins Gnotobiotic Goals Goblet Cells Health Health Benefit Human Human Genetics Immune In Vitro Inflammation Inflammatory Bowel Diseases Integration Host Factors Interleukin-10 Intestines Knockout Mice Knowledge Left Measures Metabolic Modeling Molecular Genetics Molecular Weight Mucins Mucous Membrane Mucous body substance Mus Nutrient Organoids Pathway interactions Peptides Play Polysaccharides Population Positioning Attribute Predisposition Process Production Proteins Proteolysis Proteomics Reducing diet Resort Role Series Source Soy Proteins Stable Isotope Labeling Testing Therapeutic Thick Valine Variant Volatile Fatty Acids Work bacterial metabolism branched chain fatty acid commensal bacteria cytokine deprivation dietary disorder prevention disorder risk experimental study feeding gastrointestinal genetic approach glycosylation gut bacteria gut microbiota improved in vivo insight loss of function microbial microbial community microbiome microbiota mouse model novel therapeutics pathogen prevent soy transcriptome sequencing

项目摘要

Summary The precise etiology of inflammatory bowel disease (IBD) remains unknown. Despite identification of >100 human genetic polymorphisms that are thought to play a role in IBD, genetic predisposition typically explains only a fraction of disease risk. Important contributions for environmental factors—including diet and the gut microbiota—have become prominent suspects as additional disease drivers. However, the functional interconnections between these potential contributors remain unknown. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced and metabolically characterized commensal bacteria, we have begun to elucidate the mechanistic interactions between dietary fiber, the gut microbiota and the colonic mucus barrier, which serves as a primary defense against encroachment by intestinal bacteria. During dietary fiber deficiency, the gut microbiota resorts to host- secreted mucus glycoproteins as a nutrient source, leading to erosion of the mucus layer. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. More strikingly, when this same synthetic microbiota is assembled in mice deficient in interleukin 10 (IL-10), a cytokine for which loss of function defects have been associated with human IBD, animals develop lethal spontaneous inflammation in the absence of an overt pathogen, but only on a low fiber diet. Our work has therefore revealed functional interconnections between diet, the gut microbiota, mucosal barrier function and spontaneous IBD development. Our central hypothesis is that there is a dynamic balance between fiber- and mucus-degrading bacteria, such that in low fiber conditions the mucus layer is increasingly eroded resulting in temporal disease progression that can be ameliorated by preventative or therapeutic fiber consumption or other bacterial metabolites that counterbalance inflammation. The proposed work will extend the findings outlined above by first measuring the respective contributions of mucin-degrading bacteria and their functions towards eroding the mucosal barrier and precipitating inflammation. We have already established that addition of several pure fibers to our fiber deficient diet reduces disease and have fortuitously discovered that inclusion of soy (but not milk) protein also reduces disease in part by promoting production of the branched chain fatty acid isobutyrate. Isobutyrate is produced from L-valine and our hypothesis is that soy protein delivers a peptide-based source of this amino acid to the colon for bacterial metabolism. Because isobutyrate is a poorly studied metabolite, we will investigate its microbial source(s) and mechanism of action in dampening host inflammation. We anticipate that our findings will provide functional insight into the constellation of genetic and environmental triggers that conspire to precipitate IBD. As such, our findings will provide paths to future research in humans, which are built on a foundation of functional knowledge of diet-microbiota interactions gathered in a tractable model.

概括炎症性肠病（IBD）的精确病因仍然未知。尽管确定了> 100 被认为在IBD中起作用的人类遗传多态性通常会解释只有一小部分疾病风险。环境因素的重要贡献 - 包括饮食和肠道微生物群 - 作为其他疾病驱动因素，已成为著名的嫌疑人。但是，功能这些潜在贡献者之间的互连仍然未知。使用gnotobiotic小鼠模型哪些动物用由完全测序和代谢表征的共生细菌，我们已经开始阐明机械相互作用在饮食纤维，肠道菌群和结肠粘液屏障之间，它是主要防御反对肠道细菌的侵占。在饮食纤维缺乏症中，肠道菌群诉诸宿主 - 分泌的粘液糖蛋白作为营养源，导致粘液层侵蚀。饮食纤维剥夺以及纤维剥夺的粘液擦除微生物群，可促进上皮通道和粘膜病原体的致命结肠炎，柠檬酸啮齿动物。更引人注目的是，当同样的合成微生物群在缺乏白介素10（IL-10）的小鼠中组装，这是一种细胞因子的功能缺陷损失与人类IBD有关，动物在没有的情况下发展致命的赞助者感染明显的病原体，但仅在低纤维饮食上。因此，我们的工作揭示了功能互连在饮食之间，肠道菌群，粘膜屏障功能和赞助IBD发展之间。我们的中心假设是纤维和降解细菌之间存在动态平衡，使得在低纤维中纤维条件粘液层越来越侵蚀，导致暂时性疾病进展通过预防或治疗纤维消耗或其他平衡的细菌代谢来改善炎。拟议的工作将通过首先测量亲戚来扩展上述发现粘液降解细菌的贡献及其功能在侵蚀粘膜屏障和炎症。我们已经确定了在我们的纤维中添加几个纯纤维饮食不足会减少疾病，并幸运地发现，包括大豆（但不是牛奶）蛋白部分通过促进分支链脂肪酸等丁酸的产生来减少疾病。异丁酸是由L-缬氨酸产生的，我们的假设是大豆蛋白提供了基于肽的氨基的来源酸到结肠进行细菌代谢。因为异丁酸是研究不良的代谢物，所以我们将研究其微生物源和在破坏宿主注入的作用机理。我们期待我们的发现将提供有关遗传和环境触发者星座的功能见解共同促进IBD。因此，我们的发现将为人类的未来研究提供途径，建立在饮食菌相互作用的功能知识的基础上，该知识以可拖动的模型聚集在一起。